PROJECT SUMMARY Cardiovascular disease (CVD) and Type 2 diabetes (T2D) are increasing in all developed and developing countries, but the increase is especially severe in people of Mexican ancestry, whether in the US or in Mexico. It is understood that these increases are due in part to effects of excess or unhealthy nutrition, implying that variation in cardiometabolic disease risk may be due to variation in the capacity to manage a nutritional load. However, few studies have examined postprandial metabolism, where this variation should be most evident. Our colleagues in the GEMM Family Study (Gentica de las Enfermedades Metablicas en Mxico, or Genetics of Metabolic Diseases in Mexico), a multi-center study conducted by 10 university-based teaching hospitals, have an ongoing recruitment of healthy urban adults who volunteer for a novel meal challenge. Each participant receives a mixed meal, representing a healthy combination of carbohydrate, fats, and protein, individually dosed as 30% of daily energy expenditure, and provides a timecourse series of blood and tissue biopsy samples at fasting and for 5 hours after the meal. In this study, we propose to conduct comprehensive molecular profiling, including conventional biochemical phenotypes in blood (insulin, glucose, free fatty acids, etc.) to define variation in postprandial response, plus comprehensive metabolomic profiling in blood and transcriptomic, proteomic, and metabolomic profiling in skeletal muscle, a key tissue for insulin response and utilization of carbohydrate and free fatty acids. We expect to characterize postprandial response at unprecedented resolution ? establishing individual trajectories of established and novel biomarkers of metabolic activity in blood and using combined ?omics? data to identify pathways and genes involved in postprandial response in muscle. We expect this information to help us define the range of variation in metabolic flexibility, and therefore the risk of cardiometabolic disease, in nominally healthy individuals. We further expect to identify novel biomarkers of cardiometabolic risk and to expand our knowledge of the biological mechanisms of metabolic flexibility, as a basis for novel approaches to preventing and treating these serious pathologies in a population at elevated risk of CVD and T2D. These findings should have a positive impact on public health initiatives for dealing with these serious conditions, both in Mexico and in the rapidly- growing Mexican American community.